ABSTRACT. Sensory signaling relies on the prototypical pathway mediated by the heterotrimeric G- proteins, which relays the incoming extracellular signals from the transmembrane G- protein-coupled receptors (GPCRs) to the enzymes of the second messenger system. Functional defects in these cascades lead to a variety of neurodegenerative disorders, which include retinopathies. In addition, GPCRs are among the most important targets of therapeutic intervention, which account for nearly 50% of drugs on the market. Despite recent progress in understanding the universal molecular mechanism of G-protein activation, the biological role of the G-protein beta-gamma subunit complex, and its exact role during signal transfer from a GPCR to a G-protein remain surprisingly obscure. Due to the existence of multiple beta and gamma subunit isoforms in a typical cell and the redundancy of the G-protein-mediated pathways many fundamental questions of beta-gamma complex biology have been very difficult to address under the physiological conditions. Thus, major aspects of how this protein complex functions remain unproven. This proposal builds on our strong groundwork that led to the discovery that the beta-gamma complex confers the ability of retinal rod photoreceptors to amplify visual signals and determines the overall sensitivity of these sensory neurons to light, as well as modulates signal inactivation and light adaptation. Our studies challenge a rather narrow current view of the beta-gamma complex as an auxiliary subunit of the G-protein and aim at identifying the biological role of this protein complex, its exact role during signal transfer from a GPCR to a G-protein, especially during the key activating step of this reaction ? nucleotide exchange on the G-protein alpha subunit. By using a combination of biochemical, physiological and molecular biophysical approaches, and by employing several unique mouse lines, we expect to unravel the contribution of the beta-gamma complex in the underlying mechanisms that are critical to GPCR signaling and regulation in retinal photoreceptors. As beta-gamma complex has emerged as a new target of drug design and therapeutic intervention, this proposal will lead to better understanding of how new therapies may affect GPCR signaling.